Glaucoma is the largest cause of irreversible blindness in the world and is characterized by the loss of retinal ganglion cells (RGCs), which transmit visual information from the eye to the brain. While the exact cause of glaucoma is unknown, recent evidence has shown that early menopause in women is linked with developing glaucoma. Further, mutations in estrogen receptors and polymorphisms in the estrogen metabolic pathway are linked with glaucoma in both genders. However, since the number of woman veterans has nearly doubled in the last ten years, the VA recently formed the Women?s Veterans Health Research Network (WVHRN) to help focus attention on research and treatments for this increasing population in the veteran population. These data highlight that estrogen plays a vital role in the development of glaucoma and is an important issue in the VA; however, the mechanism(s) underlying estrogen?s effects are unknown. We hypothesize that an estrogen deficiency contributes to the etiology of glaucoma by altering ocular biomechanics, increasing an individual?s risk for developing glaucoma. In this study, we will investigate the link between estrogen and glaucoma through three Specific Aims. In our first specific aim, we will measure the impact of menopause on ocular compliance and scleral mechanical properties in pre- and post-menopausal young (3-4 month) and aged (9-10 month) female rats. This will allow us to assess how estrogen deficiencies alter the biomechanical properties of the eye, which may impact RGC survival. In our second specific aim, we will evaluate the effect of early and late menopause in rats with experimental glaucoma/ocular hypertension. Specifically, over 12 weeks, we will investigate functional visual impairment (e.g. visual acuity and contrast sensitivity), RGC function and anatomical changes in the eye due to experimental glaucoma. Further, we will investigate the potential therapeutic benefits of estrogen in female and male rats with experimental glaucoma. This will allow us to determine whether estrogen therapy can preserve visual function after inducing experimental glaucoma. Our third specific aim will examine the impact of menopause on inflammatory markers and protease expression in the eye. We will also assess if the inhibition of inflammatory and protease expression prevents changes in ocular compliance associated with menopause. This investigates the potential mechanism(s) that an estrogen deficiency induces changes in ocular biomechanical properties. Our preliminary data support this overall hypothesis. We expect to build off these strong data and find that menopause will differentially influence the biomechanical properties of the eye, with young animals having a larger impact from an estrogen deficiency. We also anticipate finding that post-menopausal rats have more severe visual impairment compared to pre-menopausal rats and that estrogen therapy will preserve visual function in post-menopausal females and aged male with experimental glaucoma. Lastly, we believe that menopause will increase inflammatory markers and protease expression and that inhibiting these changes after menopause will preserve ocular biomechanical properties. These data will provide the first clear picture of how estrogen modulates the risk of developing glaucoma. If we are successful in our aims, these finding will motivate the development of estrogen as a novel therapeutic treatment for glaucoma. Overall, this study will provide information on how estrogen is linked to glaucoma and motive us to develop future studies that will investigate estrogen as a novel therapeutic treatment for glaucoma of female and male veterans in the VA clinical population. This meets the Rehabilitation Research and Development goal of preventing and treating vision loss. This CDA2 will aid in the ongoing training of the postdoctoral candidate to become an independent and successful investigator in the fields of visual neuroscience, biomechanics and glaucoma within the VA environment.